1. DES In-Stent Restenosis:
Mechanisms, Frequency, Clinical Outcomes, and Treatment Alternatives
Ron Waksman, MD
Washington Hospital Center

2. Ron Waksman, MD DISCLOSURES Consulting Fees Grants/Contracted Research
Abbott Vascular, Biotronik, Medtronic CardioVascular, Inc, Boston Scientific Corporation
Grants/Contracted Research
Abbott Vascular, Biotronik, Boston Scientific Corporation, The Medicines Company, GlaxoSmithKline, Schering-Plough, sanofi-aventis U.S. LLC

3. Mechanism of DES Restenosis
Biological factors
Drug resistance
Hypersensitivity
Mechanical factors
Non uniform stent strut distribution
Stent fractures
Polymer peeling
Non uniform drug deposition
Technical factors
Incomplete stent expansion
Stent gaps or “misses” (uncovered lesion segments)
Barotrauma to unstented segments

4. Do Patterns of in-stent restenosis predict outcomes in the DES era?
Focal (N = 132) Repeat DES 57.1%, POBA 42.9%
Non focal (N = 71) Repeat DES 69%, POBA 31%
P=0.11
Clinical median 13.7 months
P=0.04
P=0.25
P=0.69
P=0.12
Cosgrave J. et al. JACC 2006;47:

5. DES fractures a a’ Post Follow-up b b’ Stent c Restenosis c’
Aoki J. et al. CCI 2007;69: 380-6

6. Incidence and clinical presentation of stent fractures
Among 188 pts with DES restenosis,
stent fracture was identified in 35 (18.5%) cases. % %
Shaikh F et al. TCT 2006

7. Lack of Traditional Correlates for recurrence of ISR
From 2003 to 2007, 535 patients presenting with angiographic ISR after DES implantation were included. Of these, 396 patients completed 1-year follow-up
The primary endpoint was defined as clinically driven target lesion revascularization (TLR) at 1-year follow up
Stepwise manner multivariable analysis (retention criteria p< 0.2) was used to determine predictors of recurrent ISR at 1-year follow-up

8. Non-adjusted predictors of recurrent ISR at 1-year follow-upHR
95% CI
Valor P
Age
1.0
0.9
Presentation with AMI
3.1
0.03
Diabetes
0.6
Chronic renal failure
1.1
0.7
Baseline Us-CRP
0.003
Prior VBT failure
1.3
Ostial location
1.4
Type C lesion, AHA/ACC
0.5
0.3
Therapy option
VBT
0.8
0.4
c-PCI
Diffuse ISR (> 10 mm)
1.7
0.2-13
Focal ISR (< 10 mm)
1.9
0.3-14
Stent diameter

9. DES Restenosis Therapeutic approaches
Conventional POBA, Cutting Balloon
Same versus Different DES
Vascular Brachytherapy
Drug Eluting Balloon
CABG

10. Do patterns of in-stent restenosis predict outcomes in the DES era?
Cosgrave J. et al. JACC 2006;47:

11. Vascular Brachytherapy: Effective Treatment for Patients with Drug-eluting Stent Restenosis
Focal stenosis ≤10 mm, diffuse stenosis >10 mm, or proliferative stenosis.
Bonelloo, Waksman et al. J Interv Cardiol. 2008

12. Radiation (IRT) vs DES for DES Failures Results form the RESCUE Trial
Clinical 8 months
15.0
IRT (N = 61)
DES (N = 50)
p = 1.0
10.0
10.0
8.0 %
p = 0.59
p = 1.0
5.0
4.0
2.0
2.0
2.0
0.0
0.0
0.0
Death
Q-MI
TLR
Late
thrombosis
Torguson R. et al. Am J Cardiol 2006;98:1340-4

13. Washington Hospital Center, Washington, DC
Treatment of Drug-Eluting Stent Restenosis with the Same or Different Drug-Eluting Stent: To Switch or not to Switch
Kimberly Smith Kaneshige, Rebecca Torguson, Zhenyi Xue, Daniel H. Steinberg, Tina L. Pinto Slottow, Probal K. Roy, Saquib Samee, Joseph Lindsay, Augusto D. Pichard, Lowell Satler, William O. Suddath, Kenneth Kent, Ron Waksman
Washington Hospital Center, Washington, DC

14. Initial DES implantation Presentation with angiographic restenosis
Study Design
Initial DES implantation
SES n= 132, PES n=34
Total n=166
Presentation with angiographic restenosis
Same DES
SES for SES failure n=81,
PES for PES failure n=9
Total n=90
Other DES
PES for SES failure n= 51
SES for PES failure n=25
Total n= 76
12 Month clinical outcomes
Same DES n=70, Other DES n=68
Total n=138

15. Indication for Implantation of Failed DES
Clinical Indications (%)
Same DES
n=90
Other DES
n=76
p Value
Stable Angina
35.6
32.9
0.719
Unstable Angina
40.0
39.5
0.945
Silent Ischemia
6.7
9.2
0.543
ST-elevation Myocardial Infarction
11.1
7.9
0.484

16. 12 Month Similar Between Same versus Other DES

17. Same DES vs other DES vs other treatment for DES Failures Does the switch therapy work?
Cosgrave J. et al. AHJ.2007;153: 354-9

18. SES vs PES for SES Failures Multicenter Registry in Asia
1 year
1 year % %
P<0.05
P<0.05
N=198 lesions
N=161 lesions
N=156 pts
N=152 pts
Nakamura S. et al. ACC 2007

19. Same DES vs other DES vs. other treatment for DES Failures Does the switch therapy work?
Clinical 1 year %
P=0.81 40
P=0.70 35
32.6
30.8 30
26.8
Same DES
N=43 20
P=0.62
P=0.24
Different DES
N=40 10
7.5
7.7
2.7
Death
Q-MI
TVR
MACE
Garg S. et al. CCI. 2007;70: 9-14

20. Late loss in-segment - comparison Paccocath ISR I with ISAR DESIRE
Paccocath ISR I study
Late loss in-segment - comparison Paccocath ISR I with ISAR DESIRE
*data from ISAR DESIRE; Kastrati, JAMA 2005; 293: 20

21. Drug Eluting Balloon
Paccocath ISR I vs. II
Late lumen loss in-segment

22. Paccocath ISR I/II - MACE
TLR, MI, acute/subacute closure, stroke, or death
Mantel-Cox log-rank test; p-values adjusted according to Fisher’s method of combining independent tests

23. The Valentines trial is a unique first of it's kind registry.
The Valentine Trial A CRT DIOR Worldwide Trial DEB for ISR of BMS and DES
The Valentines trial is a unique first of it's kind registry.
From Valentines day (14. Feb. 2010) till the end of the CRT congress in Washington (23. Feb. 2010) it will enrol as many ISR cases of a previous placed stent as possible

24. Current therapeutic options according to potential mechanisms of DES restenosis
Type of restenosis
Potential mechanisms
Treatment options
Focal in-stent
Underexpansion BA
Fracture
DES, BA
Local vessel biology
DES, BA, DEB
Heterogeneous drug distribution
DES, BA, DEB VBT
Focal at stent edge
Geographic miss
DES
Plaque progression
Diffuse in-stent
Vessel biology / Drug resistance
Different DES, CABG VBT DEB
Proliferative
Different DES, VBT CABG DEB 24

25. DES Restenosis Summary
Restenosis after DES still occurs and at a disturbing frequency in the highest risk lesion/patient subsets.
Underlying mechanism of DES restenosis involve a complex interplay of biological, mechanical, and technical (operator-dependent) factors.
Strut fractures are more frequent than previously suspected, occurring most commonly at the edge of an overlap segment and they have been implicated in many clinical events, including restenosis, thrombosis, and aneurysm formation.

26. DES Restenosis Summary
The treatment of DES restenosis is based on appreciation of underlying mechanisms and can vary from simple POBA, to DES.
Drug Eluting Balloon is currently tested for this applicattion
When appropriate, VBT or CABG remains an effective therapeutic option
The absence of the traditional predictors for ISR in this population invokes the presence of unrecognized predisposed conditions